NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder

Ann Clin Psychiatry. 2020 Aug;32(3):182-196.


Background: NSI-189 phosphate (NSI-189) is a novel neurogenic molecule with pleiotropic properties, including antidepressant, procognitive, synaptoplastic, and neurotrophic activities demonstrated in preclinical studies. Its antidepressant activity is monoamine-independent. NSI-189 was previously tested in patients with recurrent major depressive disorder in an inpatient setting.

Methods: This study involved 220 patients randomized to an NSI-189 40-mg dose, NSI-189 80-mg dose, or placebo daily for 12 weeks. The study utilized the sequential parallel comparison design, in which the drug effect was tested in 2 separate stages of 6 weeks each. Herein, post-hoc analyses of the data are presented.

Results: NSI-189's antidepressant effect increased when the participants' initial baseline depression severity was dichotomized along a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 30. The NSI-189 80-mg dose showed significant benefit over placebo when utilizing the MADRS-6 (P = .046) in the subgroup of patients who were moderately depressed (MADRS < 30) but was not significant in patients who were severely depressed (MADRS ≥30). More pronounced procognitive effects were also observed in the moderate subgroup relative to the severe subgroup or the whole study group, in which 11/36 (31%), 5/36 (14%), or 7/36 (19%) of CogScreen variables significantly improved, respectively.

Conclusions: These results suggest that NSI-189 is effective as a safe adjunctive therapy, with most compelling antidepressant and procognitive benefits noted in patients with moderate depression.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aminopyridines / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neurogenesis*
  • Piperazines / therapeutic use*
  • Severity of Illness Index


  • Aminopyridines
  • NSI-189
  • Piperazines